Figure 1

(A) Synthetic scheme for the preparation of a dual drug-loaded PHMSN using the polymer gatekeeper technique; (B) Disulfide cross-linking and pH-dependent cationic charge reversal by the protonation of the diisopropylamine group; (C) two combination sets of hydrophilic and hydrophobic drugs; (D) schematic illustration of the cellular uptake, endosomal escape, and GSH-mediated stimulus for sequential drug release. Under tumoural acidic conditions (pH 6.5), positive charge reversal results in a fast cellular uptake. Further increase of the positive charge of the polymer in the endosome (pH 5.0–5.5) induces the swelling of the polymer gatekeeper, followed by the release of hydrophilic Ver, and facilitates the endosomal escape of the nanoparticles. In the presence of intracellular GSH, the second drug, hydrophobic Dox, is released to kill the Dox-resistant cells.